Method for treating glaucoma by the topical administration of selectively metabolized beta-blocking agents

ABSTRACT

A method for the treatment of glaucoma or lowering intraocular pressure in a mammal, involving topically administering to the eye of such mammal a selectively metabolized beta-blocking compound of the formula ##STR1## wherein R may be lower alkyl, lower alkynyl aryl, or aralkyl; A may be a direct bond, lower alkylenyl, or lower alkenyl; x may be an integer from 1 to 3; Ar may be substituted or unsubstituted aromatic; R 1  may be lower alkyl, lower hydroxy alkyl, lower alkenyl, lower alkynyl, or aralkyl; and pharmaceutically accepted salts thereof. Because of a relatively long duration of action of such compounds in ocular fluids and a relatively short duration of action in the systemic circulation, such compounds are useful for the treatment of excessive intraocular pressure without substantial systemic side effects.

This is a division of application Ser. No. 276,658, filed June 23, 1981,now U.S. Pat. No. 4,454,154, issued June 12, 1984.

BACKGROUND OF THE INVENTION

The present invention relates to a method for the treatment of glaucoma.More particularly, the invention relates to a novel method of treatmentof glaucoma or lowering of intraocular pressure by topicallyadministering beta-adrenergic blocking agents to the eye.

Glaucoma is a condition of the eye characterized by increasedintraocular pressure. Untreated, the condition can eventually lead toirreversible retinal damage and blindness. Conventional therapy forglaucoma has involved topical administration of pilocarpine and/orepinephrine, administered to the eye several times daily.

Various beta-blocking agents may also be used to lower intraocularpressure. Such use is described, for example, in reviews by W. P. Bogerin Drugs, 18, 25-32 (1979) and by T. J. Zimmerman & W. P. Boger in Surv.Ophthalaol., 23(c), 347 (1979). The use of beta-blockers for thetreatment of glaucoma is also described in the patent literature. Forexample, U.S. Pat. No. 4,195,085 to Stone discloses a method fortreatment of glaucoma by the ocular administration of a beta-blockingcompound, timolol maleate. U.S. Pat. No. 4,127,674 discloses treatingglaucoma with labetalol, a known antagonist of both alpha and betaadrenergic receptors. However, these methods also possess significantdrawbacks, in that the absorption of the beta-blocking compound into thesystemic circulation can cause undesirable side effects. Such sideeffects result from prolonged beta-blocking action on the heart,bronchioles and blood vessels. For example, according to Physicians'Desk Reference, Charles E. Baker, Jr., 35th Edition, 1981, p. 1233,adverse reactions to the topical use of timolol maleate can includebronchospasm, heart failure, as well as cardiac conduction defects.Accordingly, there is a need for a method of treatment for glaucoma orfor lowering intraocular pressure utilizing beta-blocking agents whichare relatively free of unwanted systemic side-effects.

Certain beta-blocking agents which contain enzymatically labile estergroups are known to exhibit short-acting beta-blocking effects in thesystemic circulation. Such short-acting beta-blocking compounds (SABBs)have been suggested for treatment or prophylaxis of cardiac disorders asa means for reducing heart work or improving rhythmicity for a shortduration. Such short-acting beta-blocking compounds avoid the sometimescounterproductive effects of conventional beta-blocking agents, whoseeffects are typically long-lived and, therefore, difficult to preciselycontrol.

SUMMARY OF THE INVENTION

In accordance with the present invention, disclosed herein is a methodfor the treatment of glaucoma or for lowering intraocular pressure in amammal, comprising topically administering to the eye of such mammal abeta-blocking compound of the formula: ##STR2## wherein R is loweralkyl, lower cycloalkyl, lower alkenyl, lower alkynyl lower alkyl oraryl carboxymethyl, lower haloalkyl, aralkyl or aryl; A is a directbond, lower alkylenyl, or lower alkenyl; x is an integer from 1 to 3,provided that when x is greater than 1, different occurrences of the##STR3## group may be the same or different; Ar is unsubstitutedaromatic or aromatic substituted with lower alkyl, lower alkenyl, loweralkynyl, lower alkoxy, halogen, acetamido, amino, nitro, loweralkylamino, hydroxy, lower hydroxyalkyl or cyano; R₁ is lower alkyl,lower hydroxyalkyl, lower alkenyl, lower alkynyl or aralkyl; or apharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The above-mentioned short-acting beta-blocking compounds effectivelyreduce intraocular pressure in the eyes of mammals when topicallyadministered. Because of their short-lived duration of action in thesystemic circulation, side-effects produced by their migration out ofthe eye are consequently reduced. It has further been discovered thatcertain of these compounds show an increased longevity of effect whenpresent in the ocular fluid, compared to the duration of their systemiceffects. Consequently, the present invention resides in the treatment ofglaucoma or lowering intraocular pressure with a beta-blocking compoundwhich exhibits relatively long duration of action while in the ocularfluid, but which is subject to relatively rapid breakdown into inactivemetabolites upon passage to the systemic circulation.

Compounds administered by the method of the present invention arerepresented by the formula: ##STR4## wherein R represents lower alkyl ofstraight or branched carbon chains from 1 to about 10 carbon atoms,lower cycloalkyl of from 3 to about 5 carbon atoms, lower alkenyl offrom 2 to about 5 carbon atoms, lower alkynyl of from 2 to about 5carbon atoms, lower alkyl carboxymethyl in which the alkyl portioncontains from 1 to about 5 carbon atoms, aryl carboxymethyl in which thearyl portion contains from 6 to about 8 carbon atoms, aryl of from 6 toabout 10 carbon atoms or aralkyl wherein the alkyl portion contains fromabout 1 to about 5 carbon atoms and the aryl portion representssubstituted or unsubstituted monocyclic or polycyclic aromatic orheterocyclic ring systems of from 6 to about 10 carbon atoms; Arepresents a direct bond between the ester group and Ar, lower alkylenylof from 1 to about 10 carbon atoms, or alkenyl of from 2 to about 10carbon atoms; x represents an integer from 1 to 3, provided that when xis greater than 1, different occurrences of the ##STR5## group may bethe same or different; Ar represents substituted or unsubstitutedaromatic, including monocyclic, polycyclic and heterocyclic ringsystems, wherein aromatic substituents include lower alkyl of from 1 toabout 10 carbon atoms, lower alkenyl of from 2 to about 10 carbon atoms,lower alkynyl of from 2 to about 10 carbon atoms, lower alkoxy of from 1to about 10 carbon atoms, halogen, acetamido, amino, nitro, loweralkylamino, of from 1 to about 10 carbon atoms, hydroxy, lowerhydroxyalkyl of from 1 to about 10 carbon atoms, and cyano; R₁represents lower alkyl of from 1 to about 10 carbon atoms, such asmethyl, propyl, hexyl, isopropyl, and the like; lower hydroxyalkyl offrom 2 to about 10 carbon atoms, such as hydroxyethyl, hydroxy-t-butyl,hydroxyisopropyl and the like; lower alkenyl of from 3 to about 10carbon atoms, such as allyl; lower alkynyl of from 3 to about 10 carbonatoms such as dimethylpropargyl and the like; or aralkyl wherein thealkyl portion contains from 1 to about 5 carbon atoms and the arylportion contains from 6 to about 10 carbon atoms, such as benzyl,phenethyl, naphthylethyl, 3,4-dimethoxyphenethyl and the like. Suchcompounds may be administered as their pharmaceutically acceptable acidaddition salts, e.g., as the hydrochloride, sulfate, phosphate,gluconate, tartrate, et cetera.

In preferred compounds, A is a direct bond, lower alkylenyl of from 3 toabout 5 carbon atoms, such as methylene, ethylene, butylene and thelike, or lower alkenyl of from 2 to about 5 carbon atoms, such asethenyl, 2-propenyl, 2-butenyl, and the like and x is 1 or 2, and inparticularly preferred compounds, Ar is phenyl, x is 1 or 2 and A is adirect bond, lower alkylenyl of from 1 to 3 carbon atoms, or loweralkenyl of 2 carbon atoms. It has been found that the compounds in whichAr is phenyl and para-substituted, beta-blocking potency and shortnessof duration of action in blood are improved when A is lower alkylenewith 1 or more carbons, i.e., the ester group is isolated from thearomatic ring by at least one methylene unit. Alternatively, incompounds in which Ar is phenyl, at least one of the ester-containinggroups, ##STR6## is advantageously in the ortho-position with respect tothe side chain. It is surprising and presently unexplained, that twoconfigurations of the compounds of the present invention,para-substitution with an ester carbonyl isolated from the aromatic ringand ortho-substitution with the ester carbonyl attached directly to thearomatic ring, provide enhanced beta-blocking potency and relativelyshort duration of action in blood.

The ester substituent, R, in preferred compounds, is lower alkyl of from1 to about 5 carbon atoms, such as methyl, ethyl, n-butyl, n-pentyl, andthe like; lower alkenyl of from 2 to about 5 carbon atoms, such asethenyl, 2-propenyl, 2-methyl-3-butenyl and the like, lower alkynyl offrom 3 to about 5 carbon atoms, such as propargyl, methylpropargyl andthe like, or lower cycloalkyl of from 3 to about 5 carbon atoms such ascyclopropyl, cyclopentyl, 2-methylcyclopropyl, and the like; R₁ ispreferably lower alkyl of from 1 to about 5 carbon atoms such as methyl,ethyl, propyl, t-butyl, pentyl and the like, lower hydroxyalkyl of from1 to about 5 carbon atoms, such as hydroxyethyl, hydroxy-t-butyl,hydroxyisopropyl and the like; lower alkynyl of from 3 to about 5 carbonatoms such as propargyl, dimethylpropargyl and the like; or aralkyl,wherein the alkyl portion contains from 1 to about 5 carbon atoms andthe aryl portion contains from 6 to about 10 carbon atoms, such asbenzyl, phenethyl, dimethoxyphenethyl, naphthylethyl, phenylbutyl, andthe like.

Preferred aromatic substituents include lower alkyl of from 1 to about 5carbon atoms, lower alkenyl of from 2 to about 5 carbon atoms, loweralkoxy of from 1 to about 5 carbon atoms, halogen, acetamido, amino,nitro, lower alkylamino of from 1 to about 5 carbon atoms, hydroxy,lower hydroxyalkyl of from 1 to about 5 carbon atoms, and cyano.Particularly preferred aromatic substituents are lower alkyl of from 1to about 5 carbon atoms, fluoro, chloro, cyano, and alkoxy.

The compounds described herein, as well as their methods of preparation,are disclosed in co-pending U.S. patent application, Ser. No. 211,345,which is hereby incorporated by reference. In addition, certain of thecompounds which may be employed in the method of the present inventionare known in the art. For instance, compounds of the above formula inwhich A is ethenyl are described in U.S. Pat. No. 4,191,765 and inJapanese unexamined patent application (Kokai) No. 7400247 (see alsoChemical Abstracts, 80, 95546W (1974)). Compounds of the above formulain which R₁ is 1,1-dimethyl-2-hydroxyethyl are described in British Pat.No. 1,364,280, and compounds in which R₁ is dimethylpropargyl aredescribed in British Pat. No. 1,450,287.

The compounds of this invention are advantageously administeredtopically to the eye in the form of a solution, ointment, or solidinsert such as is described in U.S. Pat. No. 4,195,085 to allowcontrolled or delayed release of the drug. Formulations may contain theactive compound, preferably, in the form of a soluble acid additionsalt, in amounts ranging from about 0.01 to about 10% by wt.,preferably, from about 0.5% to about 5% by wt. Unit dosages of theactive compound can range from about 0.001 to about 5.0 mg., preferablyfrom about 0.05 to about 2.0 mg. The dosage administered to a patientwill depend upon the patient's needs and the particular compoundsemployed.

Carriers used in the preparations of the present invention arepreferably non-toxic pharmaceutical organic or inorganic compositionssuch as water; mixtures of water and water-miscible solvents, such aslower alcohols; mineral oils; petroleum jellies; ethyl cellulose;polyvinylpyrrolidone and other conventional carriers. In addition, thepharmaceutical preparations may also contain additional components suchas emulsifying, preserving, wetting and sterilizing agents. Theseinclude polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000,1,500, 4000, 6,000 and 10,000, bacteriocidal components such asquaternary ammonium compounds, phenylmercuric salts known to have coldsterilizing properties and which are non-injurious in use, thimerosal,methyl and propyl paraben, benzyl alcohol, phenyl ethanol, bufferingingredients such as sodium chloride, sodium borate, sodium acetates,gluconate buffers, and other conventional ingredients such as sorbitanmonolaurate, triethanolamine, oleate, polyoxyethylene sorbitanmonopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol,thiosorbitol, ethylenediamine tetracetic acid, and the like.Additionally, suitable ophthalmic vehicles can be used as carrier mediafor the present purpose including conventional phosphate buffer vehiclesystems, isotonic boric acid vehicles, isotonic sodium chloridevehicles, isotonic sodium borate vehicles and the like.

The method of treatment of this invention advantageously involves thetopical administration of eye drops containing the active compound.Formulations for eye drops preferably include the active compound as asoluble acid addition salt in a properly buffered, sterile, aqueousisotonic solution.

The compounds employed in the method of the present invention are estergroup-containing beta-blockers that have a selective, localized,beta-blocking effect in the dye after topical administration. Suchcompounds are thought to be rapidly metabolized by plasma and/or liveresterases into inactive by-products, upon entering the systemiccirculation. It has been discovered that these same compounds arerelatively stable in ocular fluids, i.e., lacrimal fluids and aqueoushumor. Consequently, such compounds are useful for the treatment ofglaucoma or for lowering intraocular pressure since they remain stablewhen topically applied to the eye but rapidly metabolize whensubsequently absorbed into the systemic circulation.

Some of the compounds break down in the aqueous humor more rapidly thanothers. Such compounds may advantageously be employed when only atemporary reduction in intraocular pressure is desired, say fordiagnostic procedures. Longer-acting compounds are generally used foreffecting longer-term reductions in intraocular pressure, such as isdesired when treating chronic glaucoma. Thus, the method of the presentinvention provides a very useful therapeutic alternative for thetreatment of glaucoma or for lowering intraocular pressure.

The in vitro studies hereinafter described indicate that the compoundsused in the method of the present invention will undergo different ratesof enzymatic hydrolysis depending on their location within the body (seeTable I). For example, the compound of Example I is completelyhydrolyzed within 60 minutes in liver homogenate while only 0.3%hydrolyzed after one hour in aqueous humor, and only 1.3% hydrolyzedafter two hours. The compound of Example V is less stable in aqueoushumor, hydrolyzing 3.6% after one hour, 13.4% after two hours.

The present invention is further illustrated by the following exampleswhich are not intended to be limiting.

EXAMPLES I-V

The enzymatic hydrolysis rates of the following compounds were examinedin dog blood, liver homogenate, and aqueous humor: ##STR7##

All of the compounds tested were synthesized in accordance with theexamples of U.S. patent application Ser. No. 211,345. Acetonitrile was"HPLC" grade. Distilled water was used to dissolve the compounds and0.01N HCl was used to dissolve compounds requiring an acidic pH fordissolution.

Fresh aqueous humor was collected from eyes of dogs using a 23 gaugeneedle while fresh dog blood was collected into heparinized Vacutainer®tubes. Fresh liver was homogenized in 0.9% NaCl using a Potter-ElvehjemTeflon pestle and glass homogenizer making a 25% (W/V) homogenate.

A 0.5 ml aliquot of dog aqueous humor, blood, or liver homogenate wasincubated with 12.5 μg (0.5 ml) of beta-blocker in a Dubnoff shakingmetabolic incubator at 37° C. for 60 and 120 minutes. Denatured tissuecontrols were prepared by adding 2.0 ml of acetonitrile into 0.5 ml ofaqueous humor, blood, or liver homogenate to destroy esterase activitiesprior to addition of the beta-blockers. These controls were thenincubated at 37° C. for 120 minutes. After 60 and 120 minutes, theincubations were terminated by addition of 2 ml of acetonitrile andimmediately mixed using a Vortex® mixer to stop esterase activities.

All samples were centrifuged at 4000 RPM for 10 minutes to sedimentdenatured proteins. The resultant supernatants were transferred to WISP®vials and analyzed by high pressure liquid chromatography. Thehydrolysis of beta-blockers in aqueous humor, blood, and liverhomogenate was determined by disappearance of the compounds. The extentof enzymatic hydrolysis in each tissue was determined by comparing theamount of each compound (absolute peak area) recovered at each timepoint to the amount of each compound (absolute peak area) in denaturedtissue control and aqueous control samples.

All of the compounds examined were initially tested for chemicalhydrolysis in 0.1N potassium phosphate buffer, pH 7.40, and all werefound to be stable for at least three hours (data not shown).

Table 1 summarizes the results of these experiments. The extent ofhydrolysis is expressed in terms of the amount of each compoundrecovered after the incubation period relative to the amount of eachcompound recovered in the denatured tissue control. Most of the SABBswere readily hydrolyzed very rapidly (55.5-98.8% in 120 minutes) whenincubated with dog blood and liver homogenate. In contrast, all of thecompounds tested were resistant to enzymatic hydrolysis by esterases indog aqueous humor having hydrolysis rates of 0.3-3.6% in 60 minutes and1.3-13.4% in 120 minutes.

EXAMPLE VI

The intraocular pressure lowering effect of the compounds of thisinvention are demonstrated in rabbits with normotensive eyes.

Sterile, isotonic saline solutions of each of the compounds used inprocedures of Examples I, II, III, IV, and V are prepared by dissolving10, 30 and 100 mg. samples of each of the active compounds in 1 ml. ofsaline to give 1%, 3% and 10% solutions with pH about 6.0-7.0. Freeamines require one equivalent of HCl to effect dissolution.

The intraocular pressure lowering effect of each compound is determinedby treating the eyes of healthy rabbits with the above solutions. Threerabbits are used to evaluate the effect of each drug concentration. Astandard dose of 50 μl. of each drug solution is applied to one eye ofeach of the three rabbits. Intraocular pressure of both eyes is measuredwith a pressure tonograph or a Mackay-Marg Tonometer before drugadministration and at 15, 30, 45, 60, 120, 180, 240, 300, 360, 420 and480 min. after dosing. Control rabbits are treated similarly withsterile isotonic saline solution. Intraocular pressure lowering in thetreated dyes is compared with the untreated eyes, with saline treatedeyes and with predrug pressures. All of the test compounds showintraocular pressure-lowering activity.

EXAMPLE VII

The experiment of Example VI is repeated in all essential details,except that the following compounds are tested: ##STR8## Each of thetest compounds exhibit intraocular presssure-lowering activity.

EXAMPLE VIII

The experiment of Example VI is repeated in all essential details,except that rabbits which have corticosteroid induced ocularhypertension, as described by Bonomi, L., et al., Glaucoma, Eds. R.Pittscrick, A. D. S. Caldwell, Academic Press, New York, pp. 98-107(1980), are substituted for the normotensive rabbits. Each of the testcompounds exhibit intraocular pressure-lowering activity in this model.

                  TABLE 1                                                         ______________________________________                                        ENZYMATIC HYDROLYSIS OF SABBs BY DOG BLOOD,                                   LIVER HOMOGENATE, AND AQUEOUS HUMOR                                                     % HYDROLYZED.sup.1                                                                                AQUEOUS                                                   BLOOD    LIVER      HUMOR                                           COMPOUND    60     120     60   120   60   120                                OF EXAMPLE  min    min     min  min   min  min                                ______________________________________                                        I           76.6   94.9    100  100   0.3  1.3                                II          32.0   55.5    100  100   1.5  7.3                                III         69.0   89.4    100  100   2.4  7.5                                IV          65.7   88.5    11.9 40.0  3.6  8.2                                V           85.6   98.8    100  100   3.6  13.4                               ______________________________________                                         .sup.1 Data at each time point are expressed relative to denatured tissue     control.                                                                 

What is claimed is:
 1. A method for treating glaucoma or for loweringintraocular pressure in a mammal, which comprises topically applying tothe eye of such mammal an intraocular pressure-lowering effective amountof a compound represented by the formula: ##STR9## wherein R representslower alkyl of straight or branched carbon chains from 1 to about 10carbon atoms, lower cycloalkyl of from 3 to about 5 carbon atoms, loweralkenyl of from 2 to about 5 carbon atoms, lower alkynyl of from 2 toabout 5 carbon atoms, lower alkyl carboxymethyl in which the alkylportion contains from 1 to about 5 carbon atoms, aryl carboxymethyl inwhich the aryl portion contains from 6 to about 8 carbon atoms, aryl offrom 6 to about 10 carbon atoms or aralkyl wherein the alkyl portioncontains from about 1 to about 5 carbon atoms and the aryl portionrepresents substituted or unsubstituted monocyclic or polycyclicaromatic of from 6 to about 10 carbon atoms; A is a direct bond, loweralkylene or lower alkenylene; x is an integer from 1 to 3, provided thatwhen x is greater than 1, different occurrences of the ##STR10## groupmay be the same or different; Ar is phenyl or napthyl substituted withacetamido, amino, nitro, lower alkylamino, hydroxy, lower hydroxyalkyl,or cyano; R₁ is lower alkyl, lower hydroxyalkyl, lower alkenyl, loweralkynyl, or aralkyl; or a pharmaceutically acceptable salt thereof. 2.The method of claim 1 wherein A is a direct bond, an alkylene group offrom 1 to 5 carbon atoms or alkenylene of from 2 to about 5 carbonatoms, and x is 1 or
 2. 3. The method of claim 1 wherein Ar is phenylsubstituted with acetamido, amino, nitro, lower alkylamino, hydroxy,lower hydroxyalkyl, or cyano; x is 1 or 2, A is a direct bond, analkylene group of from 1 to about 3 carbon atoms, or alkenylene of from2 to about 3 carbon atoms and at least one of the ##STR11## groups is inthe ortho position with respect to the ##STR12## group.
 4. The method ofclaim 1 wherein Ar is phenyl substituted with acetamido, amino, nitro,lower alkylamino, hydroxy, lower hydroxyalkyl, or cyano; x is 1 or 2; Ais alkylene of from 1 to about 3 carbon atoms, or alkenylene of from 2to about 3 carbon atoms and at least one of the ##STR13## groups is inthe para position with respect to the ##STR14## group.
 5. The method ofclaim 3 wherein R is lower alkyl of from 1 to about 5 carbon atoms. 6.The method of claim 4 wherein R is lower alkyl of from 1 to about 5carbon atoms.
 7. The method of claim 1 wherein the compound is of theformula ##STR15## wherein A is an alkylene group of from 1 to about 3carbon atoms, or alkenyl of from 3 to about 5 carbon atoms; R is loweralkyl of from 1 to about 5 carbon atoms, lower alkenyl of from 2 toabout 5 carbon atoms, or lower alkynyl of from 3 to about 5 carbonatoms; Y is acetamido, amino, nitro, lower alkylamino of from 1 to about5 carbon atoms, hydroxy, lower hydroxyalkyl of from 1 to about 5 carbonatoms or cyano; and R₁ is lower alkyl of from 1 to about 5 carbon atoms,lower hydroxyalkyl of from 2 to about 5 carbon atoms, lower alkenyl offrom 3 to about 5 carbon atoms, or aralkyl wherein the alkyl portioncontains from 1 to about 5 carbon atoms and the aryl portion containsfrom 6 to about 10 carbon atoms.
 8. The method of claim 1 wherein thecompound of the formula: ##STR16## wherein A is alkylene of from 1 toabout 3 carbon atoms, R is lower alkyl of from 1 to about 5 carbonatoms, lower alkenyl of from 2 to about 5 carbon atoms or lower alkynylof from 3 to about 5 carbon atoms; Y is acetamido, amino, nitro, loweralkylamino of from 1 to about 5 carbon atoms, hydroxy, lowerhydroxyalkyl of from 1 to about 5 carbon atoms or cyano; and R₁ is loweralkyl of from 1 to about 5 carbon atoms, lower hydroxyalkyl of from 2 toabout 5 carbon atoms, lower alkynyl of from 3 to about 5 carbon atoms,or aralkyl wherein the alkyl portion contains from 1 to about 5 carbonatoms and the aryl portion contains from 6 to about 10 carbon atoms. 9.The method of claim 1 wherein the applied compound is ##STR17## whereinR is methyl, ethyl or propargyl, Y is acetamido, amino, nitro, loweralkylamino of from 1 to about 5 carbon atoms, hydroxy, lowerhydroxyalkyl of from 1 to about 5 carbon atoms or cyano; and R₁ isisopropyl, t-butyl, hydroxy-t-butyl, dimethylpropargyl, or3,4-dimethoxyphenethyl.
 10. The method of claim 1 wherein the appliedcompound is ##STR18## wherein R is methyl, ethyl or propargyl, Y isacetamido, amino, nitro, lower alkylamino of from 1 to about 5 carbonatoms, hydroxy, lower hydroxyalkyl of from 1 to about 5 carbon atoms orcyano; and R₁ is isopropyl, t-butyl, hydroxy-t-butyl, dimethylpropargyl,or 3,4-dimethoxyphenethyl.
 11. The method of claim 1 wherein the appliedcompound is ##STR19## wherein R is methyl, ethyl, or propargyl, Y isacetamido, amino, nitro, lower alkylamino of from 1 to about 5 carbonatoms, hydroxy, lower hydroxyalkyl of from 1 to about 5 carbon atoms orcyano; and R₁ is isopropyl, t-butyl, hydroxy-t-butyl, dimethylpropargyl,or 3,4-dimethoxyphenethyl.
 12. The method of claim 1 wherein the appliedcompound is ##STR20## wherein R is methyl, ethyl, or propargyl, Y isacetamido, amino, nitro, lower alkylamino of from 1 to about 5 carbonatoms, hydroxy, lower hydroxyalkyl of from 1 to about 5 carbon atoms orcyano; and R₁ is isopropyl, t-butyl, hydroxy-t-butyl, dimethylpropargyl,or 3,4-dimethoxyphenethyl.
 13. The method of claim 1 wherein thecompound is administered as a solution of about 0.01% to about 10% byweight of the active ingredient in an ophthalmologically acceptablecarrier.
 14. The method of claim 1 wherein the compound is administeredas a solution of about 0.5% to about 5% by weight of the activeingredient in an ophthalmologically acceptable carrier.
 15. The methodof claim 1 wherein the unit dosage of the active compound ranges fromabout 0.001 mg to about 5.0 mg.
 16. The method of claim 1 wherein theunit dosage of the active compound ranges from about 0.05 mg to about2.0 mg.
 17. The method of claim 1 wherein the active compound iscontained in a sterile, aqueous, buffered, isotonic solution.